POS0224 A NOVEL TNFRSF1A MUTATION ASSOCIATED WITH TNF-RECEPTOR ASSOCIATED PERIODIC SYNDROME AND ITS METABOLIC SIGNATURE
Authors: J. Steiner, A. Antebi, A. Annibal, T. Kubacki
Journal: Annals of the Rheumatic Diseases (2022)

Background Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant periodic fever syndrome characterized by prolonged episodes of fever, arthralgia, myalgia, abdominal pain and erythematous rash.1 We report a new mutation in the TNFRSF1A gene which is associated with TRAPS and AA-amyloidosis. Furthermore we analyzed the metabolic changes using a metabolomics approach. Objectives To describe a novel mutation in the TNFRSF1A gene that causes TRAPS. Methods Case series. For pathogenicity predictions we used the PolyPhen-2 web-software2 and PROVEAN3. Metabolomics: Mass spectrometry was performed on patient plasma and healthy controls using an UHPLC system (Vanquish, Thermo Fisher Scientific, Bremen, Germany) coupled to an HRAM mass spectrometer (Q-Exactive Plus, Thermo Fischer Scientific GmbH, Bremen, Germany). Results A 44-year-old man (patient 1) presented to our hospital with abdominal pain, elevated inflammation parameters, renal failure and large proteinuria. Renal biopsy revealed AA amyloidosis. Further anamnesis showed he had suffered from recurrent attacks of abdominal pain with fever and elevation of inflammation markers since he was 16 years old. He also reported that his father, aunt, sister and daughter have had similar problems. His daughter (patient 2) reported recurrent episodes of abdominal pain with fever since she was 11 years old and his 46-year-old sister (patient 3) reported similar symptoms starting at 12 years of age. Upon presentation patient 3 showed proteinuria of 2000 mg/g creatinine (albuminuria 1500 mg/g creatinine) strongly indicating early renal AA-amyloidosis. All symptomatic family members underwent genetic testing that revealed the yet uncharacterized TNFRSF1A-variant c.332A&gt;G (p.Q111R). In silico analysis of the mutation by PolyPhen-2 software and PROVEAN classified the mutation as probably pathogenic culminating in the diagnosis of TRAPS. All patients received canakinumab for treatment and responded with normalization of the inflammatory parameters. Patient 3 showed a marked reduction of proteinuria after 6 months of treatment. Using a metabolomics approach we were able to detect 158 distinct metabolic compounds of which 32 were up- and 35 downregulated, respectively. Two patients were analyzed before and after treatment with canakinumab. The treatment with canakinumab, however, appears to have no effect on the metabolic changes caused by TRAPS. Significantly upregulated metabolic pathways included purine metabolism, glycolysis/glyconeogenesis, glutathione metabolism, pyrimidine metabolism and phenylalanine, tyrosine and tryptophan biosynthesis. Downregulated pathways included Aminoacyl-tRNA biosynthesis, arginine and proline metabolism, arginine biosynthesis among others. Conclusion Here we present a novel mutation in the TNFRSF1A gene that causes TRAPS and is associated with AA-amyloidosis. Canakinumab is an effective treatment in this variant and led to improvement in proteinuria in one of the patients with presumed early renal AA-amyloidosis. We observed significant changes in the metabolome in comparison to healthy controls. Treatment with canakinumab appeared to have no effect on these metabolic changes caused by TRAPS. References [1]Hull, K. M. et al. The TNF receptor-associated periodic syndrome (TRAPS): Emerging concepts of an autoinflammatory disorder. Medicine (Baltimore). 81 , 349–368 (2002). [2]Adzhubei, I. A. et al. A method and server for predicting damaging missense mutations. Nat. Methods 7 , 248 (2010). [3]Choi, Y., Craig, J. &amp; Institute, V. A Fast Computation of Pairwise Sequence Alignment Scores Between a Protein and a Set of Single-Locus Variants of Another Protein General Terms. Proc. ACM Conf. Bioinformatics, Comput. Biol. Biomed. - BCB ’12 doi:10.1145/2382936. Disclosure of Interests None declared